Background Chronic obstructive pulmonary disease （COPD） is usually complicated with mucus overproduction in airway. Recently the increased expression of the human calcium-activated chloride channel 1 （CaCC1） was f...Background Chronic obstructive pulmonary disease （COPD） is usually complicated with mucus overproduction in airway. Recently the increased expression of the human calcium-activated chloride channel 1 （CaCC1） was found to play an important role in mucus overproduction in the asthmatic airways. To investigate the relationship of CaCC1 and mucus overproduction in the airway of Chinese patients with COPD, the expressions of CaCC1, MUC5AC and mucus in bronchial tissues were examined. Methods Bronchial tissues were obtained from fiberoptic bronchoscopy and bronchial biopsy in West China Hospital from April to July in 2004. Twenty-five patients were diagnosed as the patients with COPD overproduction, and other 20 were the control subjects. The expressions of CaCC1, MUC5AC and mucin in bronchial tissues were detected by reverse transcriptase-polymerase chain reaction （RT-PCR）, in situ hybridization with digoxigenin （DIG）-Iabeled RNA probe, immunohistochemical and alcian blue-periodic acid Schiff （AB-PAS） staining, respectively. Results Compared with the control group, the stronger expressions of CaCC1 were further detected throughout the bronchial tissues from patients with COPD （P〈0.01）. Furthermore, the stronger expressions of the CaCC1 mRNA were related to the severity of airflow obstruction. Samples from COPD showed a stronger staining for MUC5AC than those in control subjects （P〈0.01） and AB-PAS staining revealed more mucins in COPD patients＇ submucosal gland comparing with that in control subjects （P〈0.01）. Expression levels of the CaCC1 mRNA were respectively negatively correlated with the patients＇ forced expiratory volume in one second （FEV~） / forced vital capacity （FVC） data, FEV1% predicted data, V50% predicted data, V25% predicted data （r=-0.43, r=-0.43, r=-0.35, r=-0.36, P〈0.01, P〈0.01, P〈0.05, P〈0.05）. While the expression levels of the CaCC1 mRNA were well correlated with the expression levels of the MUC5AC mRNA of airway epithelium and the PAS-AB stained area of submucosal glands （r=0.39, r=0.46, P〈0.05, P〈0.01）. Expression levels of the MUC5AC mRNA were negatively correlated with the patients＇ FEV1/FVC data （P=0.01）, FEV1% pred data （P=-0.01）, V50% predicted data, V25% predicted data（r=-0.53, r=-0.53, r=-0.48, r=-0.43, P〈0.01, P〈0.01, P〈0.01, P〈0.01）. While the expression levels of the MUC5AC mRNA were well correlated with the positively PAS-AB stained area of submucosal gland （P〈0.05）, and the correlation coefficients were 0.43. Conclusion These results suggest that the stronger gene expression of CaCC1 exists, complicated with mucus overproduction in the airwav of Chinese patients with COPD.展开更多
Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke.The narrow treatment time window is still to be solved.Given that the ischemic core expanded ove...Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke.The narrow treatment time window is still to be solved.Given that the ischemic core expanded over days,treatment with an extended time window is anticipated.Bestrophin1(BEST1)belongs to a bestrophin family of calcium-activated chloride channels.We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice.Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits.Using electrophysiological recordings,we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity.Finally,we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6—72 h post-ischemia in rodents.This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions.Our study identifies the glutamatereleasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.展开更多
基金the grants from Natural Science Foundation of China and from China Medical Board of New York to Dr. F.Q. Wen(No.30425007,30370627,00-722,06-838)
文摘Background Chronic obstructive pulmonary disease （COPD） is usually complicated with mucus overproduction in airway. Recently the increased expression of the human calcium-activated chloride channel 1 （CaCC1） was found to play an important role in mucus overproduction in the asthmatic airways. To investigate the relationship of CaCC1 and mucus overproduction in the airway of Chinese patients with COPD, the expressions of CaCC1, MUC5AC and mucus in bronchial tissues were examined. Methods Bronchial tissues were obtained from fiberoptic bronchoscopy and bronchial biopsy in West China Hospital from April to July in 2004. Twenty-five patients were diagnosed as the patients with COPD overproduction, and other 20 were the control subjects. The expressions of CaCC1, MUC5AC and mucin in bronchial tissues were detected by reverse transcriptase-polymerase chain reaction （RT-PCR）, in situ hybridization with digoxigenin （DIG）-Iabeled RNA probe, immunohistochemical and alcian blue-periodic acid Schiff （AB-PAS） staining, respectively. Results Compared with the control group, the stronger expressions of CaCC1 were further detected throughout the bronchial tissues from patients with COPD （P〈0.01）. Furthermore, the stronger expressions of the CaCC1 mRNA were related to the severity of airflow obstruction. Samples from COPD showed a stronger staining for MUC5AC than those in control subjects （P〈0.01） and AB-PAS staining revealed more mucins in COPD patients＇ submucosal gland comparing with that in control subjects （P〈0.01）. Expression levels of the CaCC1 mRNA were respectively negatively correlated with the patients＇ forced expiratory volume in one second （FEV~） / forced vital capacity （FVC） data, FEV1% predicted data, V50% predicted data, V25% predicted data （r=-0.43, r=-0.43, r=-0.35, r=-0.36, P〈0.01, P〈0.01, P〈0.05, P〈0.05）. While the expression levels of the CaCC1 mRNA were well correlated with the expression levels of the MUC5AC mRNA of airway epithelium and the PAS-AB stained area of submucosal glands （r=0.39, r=0.46, P〈0.05, P〈0.01）. Expression levels of the MUC5AC mRNA were negatively correlated with the patients＇ FEV1/FVC data （P=0.01）, FEV1% pred data （P=-0.01）, V50% predicted data, V25% predicted data（r=-0.53, r=-0.53, r=-0.48, r=-0.43, P〈0.01, P〈0.01, P〈0.01, P〈0.01）. While the expression levels of the MUC5AC mRNA were well correlated with the positively PAS-AB stained area of submucosal gland （P〈0.05）, and the correlation coefficients were 0.43. Conclusion These results suggest that the stronger gene expression of CaCC1 exists, complicated with mucus overproduction in the airwav of Chinese patients with COPD.
基金supported by STI2030-Major Project(2022ZD0211700,China)National Natural Science Foundation of China(82171293,82090042 and 82171368)Natural Science Foundation of Jiangsu Province(BK20211255,China)。
文摘Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke.The narrow treatment time window is still to be solved.Given that the ischemic core expanded over days,treatment with an extended time window is anticipated.Bestrophin1(BEST1)belongs to a bestrophin family of calcium-activated chloride channels.We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice.Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits.Using electrophysiological recordings,we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity.Finally,we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6—72 h post-ischemia in rodents.This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions.Our study identifies the glutamatereleasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.
